Novel synthesis of perfluoroalkylated heterocyclic compounds from α-chlorostyrenes via perfluoroalkylated α,β-unsaturated ketones

Article abstract of DOI:10.1016/S0040-4039(00)01871-2

A convenient method for the one-pot synthesis of heterocyclic compounds bearing a perfluoroalkyl group from α-chlorostyrenes via perfluoroalkylated α,β-unsaturated ketones has been developed.

Full text of DOI:10.1016/S0040-4039(00)01871-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 33–36
Novel synthesis of perfluoroalkylated heterocyclic compounds
from a-chlorostyrenes via perfluoroalkylated a,b-unsaturated
ketones
Masanori Ohkoshi, Masato Yoshida,* Haruo Matsuyama and Masahiko Iyoda*
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan
Received 16 August 2000; revised 19 October 2000; accepted 20 October 2000
Abstract—A convenient method for the one-pot synthesis of heterocyclic compounds bearing a perfluoroalkyl group from
a-chlorostyrenes via perfluoroalkylated a,b-unsaturated ketones has been developed. © 2000 Elsevier Science Ltd. All rights
reserved.
Development of an efficient method for the synthesis of
perfluoroalkylated heterocyclic compounds is currently
an important subject, especially in agrochemical and
pharmaceutical fields,1 because the fluoroalkylated het-
erocyclic compounds have high potential as herbicides,
fungicides, drugs and pesticides, etc.2 Among the vari-
ous methods, the building-block strategy is the most
popular and attractive. In our continuous work on
oxygenative perfluoroalkylation of olefins,3,4 we now
report a novel one-pot synthetic route to heterocyclic
compounds bearing a perfluoroalkyl group from a-
chlorostyrene as shown in Scheme 1.
obtained as a mixture of the unsaturated ketone (Ar-
COCHꢀCF(CF2)n−1CF3: 1) and the saturated ketone
(ArCOCH2(CF2)nCF3: 2) in the photochemical reaction
of a-chlorostyrene with perfluoroalkyl iodide in the
presence of hexabutylditin under oxygen atmosphere.4
The saturated ketone 2 was produced initially, and then
the elimination of HF gave the unsaturated ketone 1
under basic conditions. The ketone 1 is expected to be
very reactive for various types of nucleophiles.4–6 When
the ketone 1a, thus produced, was treated with
methanol or isopropylamine, the corresponding substi-
tution products (3 and 4) were obtained in high yields
(Scheme 2). The more thermodynamically stable Z
isomer was formed selectively in 3. The structure of 3
As reported previously, fluoroalkylated ketones were
Ar
Cl
CF3(CF2)n •, O2
Perfluoroalkylated
Heterocyclic Compounds
HNu–Nu'H
C
CH2
Scheme 1.
H
H
C
(CF2)4CF3
1) CF3(CF2)5I, (Bu3Sn)2 ,
(CF2)4CF3
C
Ph
Cl
Ph
Ph
NuH, Na2CO3
ether
C
O
C
hν, O2, benzene
C
O
C
F
C
CH2
Nu
2) Et3N, Na2CO3 , ether
1a
3: Nu= OMe
Yield; 88% from 1a (Z : E = 91 : 9)
4: Nu = NHCH(CH3)2
Yield; 91% from 1a
Scheme 2. Reaction of 1a with nucleophiles.
Keywords: oxygenation; fluorine and compounds; ketones; nitrogen heterocycles.
* Corresponding authors.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01871-2

34
M. Ohkoshi et al. / Tetrahedron Letters 42 (2001) 33–36
was characterized by examination of the spectroscopic
data in comparison with those of E and Z-1a.4 In 4,
one isomer was obtained selectively, and the structure
was assigned to the Z isomer based on the NꢁH…O
hydrogen bond.
Similarly, dihydrodiazepines 6 and pyrimidines 7 were
obtained in moderate yields by the reactions with ethyl-
ene diamine (NH2CH2CH2NH2) and formamidine ace-
tate (NHꢀCHNH2·AcOH), respectively (Scheme 4,
Table 1).9 In the diazepine, one tautomer (7-aryl-5-per-
fluoroalkyl-2,3-dihydro-1,4-diazepine: 6) was observed;
the structure was determined by the comparison of the
13C NMR spectra with those of 5-trifluoromethy-2,3-
dihydro-1,4-diazepine.10
Since an attempted photochemical reaction produced a
mixture of 1 and 2, we planned the synthesis of hetero-
cyclic compounds starting from the mixture of 1 and 2.
By using the new methodology, a variety of pe-
rfluoroalkylated heterocylic compounds hitherto un-
known can be expected to be prepared in very short
steps. When the reaction mixture consisting of 1 and 2
was treated with hydrazine acetate, the fluoroalkylated
pyrazole 5 was obtained (Scheme 3).7 Although the two
tautomers, 5-aryl-3-perfluoroalkyl- and 3-aryl-5-pe-
rfluoroalkylpyrazoles are possible, the NMR spectra
showed one set of signals even at −80°C. The observed
13C NMR chemical shifts were consistent with those of
5-aryl-3-perfluoroalkylpyrazole (5) in the comparison
with those of 3- and 5-phenylpyrazoles and N-
methylpyrazole reported in the literature.8 The length
of the fluoroalkyl chains and the substituents on the
benzene ring (p-Me and p-Cl) had little effect on the
yields of the pyrazoles 5 (Table 1).
Interestingly, in the reaction with cyclic hydrazine like
piperidazine, bicyclic iminium salts 8 were obtained
(Scheme 5). As the reaction was carried out in one-pot,
Bu3SnI formed by the iodine abstraction from per-
fluoroalkyl iodide with a stannyl radical in the photo-
chemical reaction, remained in the reaction system, and
the iodine became the counter anion of the salt. The
structures of these compounds were characterized by
examination of the spectroscopic and analytical data.12
Thus, the method is also applicable to secondary
amines to afford the N-alkylated pyrazoles.
Fluoroalkylated isoxazoles were obtained as a mixture
of the regioisomers 9 and 10 by the direct reaction
(CF2)n-1CF3
Ar
1) (Bu3Sn)2 , hν, O2, benzene
2) NH2NH2•AcOH, EtOH
C
CH2
+
CF3(CF2)nI
Ar
N
Cl
N
H
5
Scheme 3. Synthesis of 5.
Table 1. One-pot synthesis of 5–7 from a-chlorostyrenes via 1
Table 1
One-pot synthesis of 5 - 7 from α-chlorostyrenes via 1
(CF2)n-1CF3
HN
Ar
Ar
N
N
Ar
N
N
H
CF3(CF2)n-1
Ar
N
6
CF3(CF2)n-1
7
5
Yield / %a)
n
Yield / %a)
Ar
Yield / %a)
n
n
Ar
Phb)
Phb)
Ph
a; 3
59 (44)
65 (42)
69 (48)
a; 3
b; 5
c; 9
48 (40)
48 (37)
54 (47)
Ph
a; 3
Ph
41 (35)
43 (34)
47 (39)
45
b; 5
c; 9
Ph
b; 5 Ph
c; 9
Ph
Ph
d; 5
e; 5
57 (40)
57 (47)
54
57
p-ClC6H4
d; 5
e; 5
p-ClC6H4
d; 5 p-ClC6H4
e; 5 p-MeC6H4
p-MeC6H4
p-MeC6H4
44
a) Yields (overall yields based on CF3(CF2)nI) were determined by 19F NMR using PhCF3 as an internal standard.
Isolated yields are shown in parenthesis. b) Known compounds.11
Ar
N
Ar
Cl
HN
Ar
1) (Bu3Sn)2 , hν, O2, benzene
C
CH2
+
CF3(CF2)nI
N
or
N
2) NH2CH2CH2NH2 or NH=CHNH2•AcOH, EtOH
CF3(CF2)n-1
CF3(CF2)n-1
6
7
Scheme 4. Synthesis of 6 and 7.

M. Ohkoshi et al. / Tetrahedron Letters 42 (2001) 33–36
35
Ph
-
(CF2)n-1CF3
Ph
Cl
1) (Bu3Sn)2, hν, benzene, O2
+
+
CF3(CF2)nI
C
CH2
N
N
I
2)
HN NH
Yield a; n = 3
b; n = 5
48% (31%)
48% (34%)
42% (30%)
in MeOH
8
c; n = 9
Scheme 5. Synthesis of 8. Overall yields were determined by 19F NMR. Isolated yields are shown in parenthesis.
(CF2)4CF3
(CF2)4CF3
Ph
Cl
1) (Bu3Sn)2, hν, benzene, O2
+
CF3(CF2)4I
C
CH2
+
2) NH2OH•HCl, NaOH, MeOH
Ph
O
Ph
N
(eq. 1)
N
O
10
9
17%
13%
(CF2)4CF3
H
C
(CF2)4CF3
OMe
NH2OH•HCl, NaOH
MeOH
Ph
(eq. 2)
C
C
Ph
O
O
N
9
3
68% (40%)
Scheme 6. Synthesis of 9 and 10. Isolated yield is shown in parenthesis.
between the photochemical reaction mixture and hy-
droxylamine (Eq. (1), Scheme 6).13 On the other hand,
the ketone 3 was found to give the isoxazole 9 selec-
tively by the reaction with hydroxylamine; the one-pot
Lauterbach, C.; Burger, K. J. Fluorine Chem. 1996, 78, 55;
Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.;
Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis 1997,
1321; Funabiki, K.; Nakamura, H.; Matsui, M.; Shibata,
K. Synlett 1999, 756.
procedure for the regioselective synthesis of 9 was
1
carried out as shown in Eq. (2) of Scheme 6.14 The H
NMR chemical shift (lH=7.07) of the isoxazole 9 thus
obtained was consistent with the reported shift,15 and
the C-5 carbon in the isoxazole ring was observed at
l=158.83 as a triplet due to the CCF coupling reflect-
ing the existence of a perfluoroalkyl group on this
carbon.14
2. Filler, R.; Kobayashi, Y. Biomedicinal Aspect of Fluorine
Chemistry, Kodansha/Elsevier: New York, 1982.
3. Yoshida, M.; Ohkoshi, M.; Aoki, N.; Ohnuma, Y.; Iyoda,
M. Tetrahedron Lett. 1999, 40, 5731.
4. Yoshida, M.; Ohkoshi, M.; Iyoda, M. Chem. Lett. 2000,
804.
5. Umemoto, Y.; Kuriu, Y.; Nakayama, S.; Miyano, O.
Tetrahedron Lett. 1982, 23, 1471.
In summary, the high potential of the ketone 1 as a
building block for the synthesis of heterocyclic com-
pounds was shown. As a-chlorostyrenes were readily
6. Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1989,
30, 2049; Tang, X.-Q.; Hu, C.-M. J. Chem. Soc., Perkin
Trans. 1 1994, 2161; Tang, X.-Q.; Hu, C.-M. J. Chem. Soc.,
Perkin Trans. 1, 1995, 1039.
16
prepared from styrenes with PhSeCl3 or from ace-
tophenone derivatives with PCl5,17 the method de-
scribed here is very convenient and practical for the
regioselective synthesis of various types of heterocyclic
compounds bearing both perfluoroalkyl and aryl
groups.
7. Typical procedure for the synthesis of 5. A solution of
perfluoroalkyl iodide (0.40 mmol), a-chlorostyrene (1.20
mmol), and (Bu3Sn)2 (0.44 mmol) in 3 mL of benzene was
irradiated using a metal halide lamp (National Sky-beam
MT-70) in Pyrex tube under O2 atmosphere for 5 h. After
removal of benzene from the reaction mixture, ethanol and
hydrazine acetate were added. The resultant solution was
stirred under reflux for 2 h. The pyrazole 5 was isolated
using column chromatography on silica gel with hexane/
dichloromethane as eluent, followed by gel permeation
chromatography. Compound 5b (Ar=Ph, n=5): colorless
needles from hexane; mp 91.2–92.2°C; 1H NMR (500
MHz: CDCl3) l 6.82 (s, 1H), 7.42-7.50 (m, 3H), 7.59
(m, 2H), 11.05 (brs, 1H); 13C NMR (125.7 MHz, CDCl3)
l 102.78, 125.61, 127.94, 129.28, 129.49, 142.52 (br),
145.24; 19F NMR (376 MHz, CDCl3) l (ppm down field
from external CF3COOH) −5.44 (3F), −34.68 (2F), −
47.05 (2F), −47.41 (2F), −50.90 (2F); EI-MS (m/z) 412
(M+); HRMS 412.0430 (calcd for C14H7F11N2:
412.0433). Compound 5d (Ar=p-ClC6H4, n=5): colorless
Acknowledgements
Financial support by a Grant-in-Aid for Scientific Re-
search on Priority Areas from the Ministry of Educa-
tion, Science, Sports and Culture, Japan (11119256)
and the Fund for Special Research Project at Tokyo
Metropolitan University is gratefully acknowledged.
References
1. For a review: Tanaka, K. J. Synth. Org. Chem. Jpn. 1990,
48, 16. For recent examples: Okada, E.; Masuda, R.; Hojo,
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1
needles from hexane; mp 131.6–132.3°C; H NMR (500
MHz: CDCl3) l 6.82 (s, 1H), 7.46 (d, J=8.7Hz, 2H), 7.54
(d, J=8.7 Hz, 2H), the NH proton did not appear in

36
M. Ohkoshi et al. / Tetrahedron Letters 42 (2001) 33–36
CDCl3; 13C NMR (100.4 MHz, CDCl3) l 103.22, 126.64,
126.97, 129.60, 135.62, 142.30 (br), 144.56;19F NMR (376
MHz, CDCl3) (ppm down field from external
12. Iminium salt 8 was obtained as follows. The reaction
mixture was dissolved in CH3CN and the solution was
washed with hexane. After removal of CH3CN, the
residue was purified by gel permeation chromatography.
Compound 8 was isolated by recrystallization from hex-
ane/dichloromethane. 8b (Ar=Ph, n=5): colorless
l
CF3COOH) −5.43 (3F), −34.66 (2F), −47.03 (2F), −
47.41 (2F), −50.88 (2F); EI-MS (m/z) 446 (M+); HRMS
446.0036 (calcd for C14H6ClF11N2: 446.0043). Compound
5e (Ar=p-MeC6H4, n=5): colorless needles from hex-
1
plates; mp 163.7–164.5°C; H NMR (400 MHz: CDCl3)
1
ane; mp 159.7–160.3°C; H NMR (400 MHz: CDCl3) l
l 2.42 (m, 2H), 2.53 (m, 2H), 4.89–4.95 (m, 4H), 7.08 (s,
1H), 7.58–7.64 (m, 3H), 7.80 (m, 2H); 13C NMR (100.4
MHz, CDCl3) l 18.88, 18.92, 50.46, 50.95, 110.78, 123.88,
129.62, 129.87, 132.19, 135.30 (t, JCCF=28 Hz), 149.81;
19F NMR (376 MHz, CDCl3) l (ppm down field from
2.53 (s, 3H), 6.78 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.47
(d, J=8.0 Hz, 2H) 11.63 (brs, 1H); 13C NMR (100.4
MHz, CDCl3) l 21.27, 102.44, 125.18, 125.52, 129.95,
139.57, 142.54 (t, JCCF=29 Hz), 145.25; 19F NMR (376
MHz, CDCl3)
l (ppm down field from external
external CF3COOH) −5.22 (3F), −33.08 (2F),
−
CF3COOH) −5.45 (3F), −34.65 (2F), −47.04 (2F), −
47.38 (2F), −50.90 (2F); EI-MS (m/z) 426 (M+); HRMS
426.0580 (calcd for C15H9F11N2: 426.0590).
44.97(2F), −46.68 (2F), −50.63 (2F); FAB-MS (m/z) 594
(M+), 468 (M+−126); calcd for C18H14F11N2I: C, 36.38;
H, 2.37; N, 4.71; found: C, 36.41, H, 2.34; N, 4.72.
13. Massyn, C.; Cambon, A. J. Fluorine Chem. 1975, 5, 67.
14. The photochemical reaction mixture starting from 0.40
mmol of perfluorohexyl iodide and 1.2 mmol of a-
chlorostyrene was treated with MeOH (40 mg) in the
presence of Et3N (0.1 mL) and Na2CO3 (130 mg) in ether
(2 mL) for 2 h at room temperature. After the solvent
was changed from ether to MeOH, NaOH (80 mg) was
added, and the solution was heated at reflux for 4 h.
After evaporation of MeOH, the organic product was
extracted with benzene, and the isoxazole 9 was isolated
using column chromatography on silica gel, followed by
gel permeation chromatography. 9: colorless needles from
pentane; mp 58.5–60.4°C; 1H NMR (400 MHz: CDCl3) l
7.07 (s, 1H), 7.51 (m, 3H), 7.83 (m, 2H); 13C NMR (100.4
MHz, CDCl3) l 105.45, 126.07, 126.97, 129.19, 130.95,
158.83 (t, JCCF=32 Hz), 162.74; 19F NMR (376 MHz,
CDCl3) l (ppm down field from external CF3COOH)
−5.38 (3F), -36.43 (2F), −47.26 (4F), −50.84 (2F); EI-
MS (m/z) 413 (M+); HRMS 413.0287 (calcd for
C14H6F11NO: 413.0274).
8. Aguilar-Parrilla, F.; Cativiela, C.; de Villegas, M. D. D.;
Elguero, J.; Foces-Foces, C.; Laureiro, J. I. G.; Cano, F.
H.; Limbach, H.-H.; Smith, J. A. S.; Toiron, C. J. Chem.
Soc., Perkin Trans. 2 1992, 1737.
9. Compound 6b (Ar=Ph, n=5): yellow oil; 1H NMR (500
MHz: CDCl3) l 3.39 (brs, 2H), 4.07 (brs, 2H), 5.31 (s,
1H), 5.61 (brs, 1H), 7.40 (m, 2H), 7.45 (m, 1H), 7.50 (m,
2H); 13C NMR (125.7 MHz, CDCl3) l 48.69, 57.42,
88.59, 127.19, 128.84, 130.34, 138.51, 156.79, 157.08 (br,
t); 19F NMR (376 MHz, CDCl3) l (ppm down field from
external CF3COOH) −5.46 (3F), −38.79 (2F), −46.16
(2F), −46.89 (2F), −50.81 (2F); EI-MS (m/z) 440 (M+);
HRMS 440.0755 (calcd for C16H11F11N2: 440.0746).
Compound 7b (Ar=Ph, n=5): yellow oil; 1H NMR (400
MHz: CDCl3) l 7.54–7.60 (m, 3H), 8.05 (s, 1H), 8.17 (m,
2H), 9.42 (s, 1H); 13C NMR (125.7 MHz, CDCl3) l
114.43, 127.47, 129.29, 132.15, 135.34, 156.44 (t, JCCF
=
26 Hz), 159.20, 166.29; 19F NMR (376 MHz, CDCl3) l
(ppm down field from external CF3COOH) −5.42 (3F),
−40.57 (2F), −46.49 (2F), −46.82 (2F), −50,79 (2F);
EI-MS (m/z) 424 (M+); HRMS 424.0417 (calcd for
C15H7F11N2: 424.0433).
15. Gallucci, J.; Blanc, M. L.; Riess, J. A. J. Chem. Res. (S)
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